Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl reductase (HMG-Coenzyme A reductase; HMG-CO-A reductase), are a class of drugs widely used to lower levels of circulating LDL (low-density lipoprotein) cholesterol, or LDL-C, known as “the bad cholesterol”. The enzyme HMG-CO-A reductase plays a central role in the biosynthesis of cholesterol in the liver, which produces about 70 percent of total cholesterol in the body. Elevated LDL cholesterol level is a key risk factor for cardiovascular disease (CVD), heart attacks and strokes. Statins have been found to prevent cardiovascular disease, and heart attacks in those who are at high risk (WIKI). Besides life-style changes, such as regular exercise, eating less or avoiding fatty meals to maintain a healthy cardiovascular system, statins have become the strategic choice of treatment to achieve target LDL-C levels to prevent heart attacks, and minimize secondary or post cardiac events. Since the introduction of statins in clinical use over the last 25 years, millions of patients around the world have benefited from improved cardiovascular outcomes.
In 2013 the American College of Cardiology and American Heart Association have published widely disseminated guidelines on the use of statins (Stone N J et al., “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults”, J. of the Amer. College of Cardiology (2013), 10.1016/j.jacc.2013.11.002. Under these guidelines, more than 50 million Americans are candidates for Statin therapy (WSJ Mar. 31, 2014/B3).
The most prescribed statins are atorvastatin (Lipitor®, trademark of Pfizer); Pravastatin (Pravachol® trademark of Sankyo); rosuvastatin (Crestor® trademark of Astra-Zeneca), and simvastatin (Zocor® trademark of Merck and Co.). All these four statins, chemically, are a single diastereoisomer in the trans-3-β-hydroxy-δ-lactone portion of the molecule, which is the common key phamacophore in all the statins. The above statins are either totally synthetic (atorvastatin and rosuvastatin) or a combination of fermentation products and subsequent synthetic modifications. The effective doses range from about 10 mg to about 80 mg/day. However, in use statins are not without side-effects. Estimates are that 10-15% of people (or more than 5 million persons) suffer serious muscle pain or other side effects that prevent them from taking statins, or taking them at doses required to achieve target cholesterol levels. Rare reactions include myositis and myopathy, with the potential for rhabdomyolysis (a significant breakdown of skeletal muscle) leading to possibly acute renal failure (WIKI). Serious leg pains after prolonged use have been reported, e.g., with atorvastatin and simvastatin even at their lowest 10 mg/day dose. Thus there is a need for novel statins, which incorporate unique structural features attached to the trans-3-β-hydroxy-δ-lactone moiety of statins which have an improved safety profile than those currently used statins. It is possible that the presently conceived “omegastatins” would also concomitantly lower high triglycerides levels in addition to LDL-C.